title: 4-Amino-7-chloroquinolines: probing ligand efficiency provides botulinum neurotoxin serotype A light chain inhibitors with significant antiprotozoal activity.
abstract: Structurally simplified analogues of dual antimalarial and botulinum neurotoxin serotype A light chain (BoNT/A LC) inhibitor bis-aminoquinoline (1) were prepared. New compounds were designed to improve ligand efficiency while maintaining or exceeding the inhibitory potency of 1. Three of the new compounds are more active than 1 against both indications. Metabolically, the new inhibitors are relatively stable and nontoxic. 12, 14, and 15 are more potent BoNT/A LC inhibitors than 1. Additionally, 15 has excellent in vitro antimalarial efficacy, with IC90 values ranging from 4.45 to 12.11 nM against five Plasmodium falciparum (P.f.) strains: W2, D6, C235, C2A, and C2B. The results indicate that the same level of inhibitory efficacy provided by 1 can be retained/exceeded with less structural complexity. 12, 14, and 15 provide new platforms for the development of more potent dual BoNT/A LC and P.f. inhibitors adhering to generally accepted chemical properties associated with the druggability of synthetic molecules.
authors.affiliation: Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia.
authors.forename: Igor M
authors.initials: IM
authors.lastname: Opsenica
authors.forename: Mikloš
authors.initials: M
authors.lastname: Tot
authors.forename: Laura
authors.initials: L
authors.lastname: Gomba
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Nuss
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sciotti
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.forename: James C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Solaja
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors*; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D008024:Ligands; D011804:Quinolines; D019274:Botulinum Toxins, Type A